CN104974106B - 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate synthetic method - Google Patents
5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate synthetic method Download PDFInfo
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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Abstract
The invention discloses a kind of 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate synthetic methods, comprising: step 1: dialkyl oxalate and hydrazine hydrate, which are carried out ammonolysis reaction, obtains oxalic acid list alkyl ester hydrazides；Step 2: obtained oxalic acid list alkyl ester hydrazides and fatty acid anhydride are carried out acylation reaction, 2- hydrazide group-oxalic acid list alkyl ester is obtained；Step 3: obtained 2- hydrazide group-oxalic acid list alkyl ester is carried out dehydration condensation reaction, target product 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate is obtained.5- alkyl-[1,3,4] of the invention-oxadiazoles -2- alkyl formate synthetic method, pass through the improvement to technique itself, the reagent using virulent property and strong corrosive is avoided, and route novelty, high income, raw material and solvent are cheap, simple and safe operation, is suitable for industrialized production.
Description
Technical field
The invention belongs to technical field of organic synthesis, are specifically related to a kind of 5- alkyl-[1,3,4]-oxadiazoles -2- formic acid
The synthetic method of Arrcostab.
Background technique
5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate (compound -1) can be hydrolyzed into 5- alkyl-[1,3,4] -
Oxadiazoles -2- potassium formate (compound -2).International publication number is that 5- alkyl-is stated in the patent document of WO2006/060712A2
[1,3,4]-oxadiazoles -2- alkyl formate (compound -1) can be hydrolyzed directly in ethanol/water mixed system with potassium hydroxide
Obtain 5- alkyl-[1,3,4]-oxadiazoles -2- potassium formate (compound -2).
Compound -2 can be used for constructing the inhibitor of hiv integrase, such as the international publication number of Merck company application is
The Raltegravir (Merck, MK-0518, R2=CH3) that is stated in the patent document of WO2006/060712A2 and its similar
Object.It can also be used to new one that construction Concert Pharmaceuticals company states in US2009/0035324A1
The compound of race's hiv integrase inhibitor.
5- alkyl-[1,3,4]-oxadiazoles -2- formic acid esters (compound -1) can be prepared by two different methods
It obtains.One is 5- substituted tetrazole removing nitrogen and rearrangement obtains (route 2), and another method is by N, and N'- is asymmetric
The dehydration condensation of diacyl hydrazide (route 3 and route 4) obtains.
Route 1 divides three steps: the first step is the preparation of key intermediate 5- substitution -1H- tetrazole (compound -3).Second step
Reaction is that the selection of the position N-2 of 5- substitution -1H- tetrazole is acylated, and third step reaction is acylate (compound -4) through overweight
Row obtains 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate (compound -1).
Synthesize 5- substituted tetrazole (compound -3) typical method (W.G.Finnegan et al,
J.Am.Chem.Soc.1958,80:3908) it is nitrile and sodium azide or ammonium azide in DMF/DMSO, in 100-125 DEG C
It is reacted under high temperature.Its starting material either sodium azide or ammonium azide are high poison and explosive chemicals, Er Qie
In reaction process, in last handling process, reaction mass can gradually generate in acid condition hydrazoic acid (it is a kind of at room temperature without
Color, unstable, great volatile liquid), thus this reaction industry metaplasia production be it is abnormally dangerous, have severe compromise
Chemical Manufacture.So also resulting in it securely generates that management cost is high, and product price is higher, product downstream
Production cost also correspondinglys increase.
In past 50 years, a series of improvement is had also been made in the synthesis of 5- substituted tetrazole (compound -3).The patent No.
A method is disclosed for the patent document of US5502191: at DMF(BP.154 DEG C) in, 5 times of sodium azide measured and nitrile are returning
It is reacted 36 hours at a temperature of stream；K.Koguro et al., (Synthesis, 1998,910) disclose a better method:
With aromatic solvent instead of aprotic polar solvent, such as DMF, DMSO.These solvent prices are high, it is not easy to be recycled.But
It is that these methods have still used excessive sodium azide, and the reaction time is longer, and reaction temperature is still higher.
Z.P.Demko and K.B.Sharpless(J.Org.Chem., 2001,66:7945) propose new improved side
Method: reaction can carry out in water.But reaction wants could complete for 24-48 hours, some embodiment 5- substituted tetrazole (chemical combination
Object -3) preparation require under high pressure, up to can just complete to react at 170 DEG C.
J.Roh et al. (Synthesis, 2009,2175) report in mention: can be very short under microwave radiation when
Between (1-12 hours) reset, yield is also higher.But the capacity maximum of microwave radiation reaction can only arrive a hundreds of grams of left sides at present
Right inventory, is not suitable for large-scale industrial production.
The above 5- substituted tetrazole preparation process amelioration be reduced in terms of raw materials for production cost technique at
This, but the safety of technique, the security risk of azido compound do not completely eliminate, so the safety management cost and wind of production
Danger is still very high.
Second step reaction is 5- substituted tetrazole (compound -3) and monoalkyl oxalyl chloride (is also one kind for mass production
Expensive reagent) selectively acylating N-2 obtain [2- (5- alkyl-tetrazole)] carbonylic acetic acid ester (compound -4).In this
Mesosome can be directly used for next step rearrangement reaction.Reactant is heated to 60-65 DEG C and keeps the temperature 1 hour, the nitrogen to largely escape
After calming down, reaction substantially completely, and obtains after conventional post-processing the world that compound -1(applies referring to Merck company
Notification number is the patent document of WO2006/060712A2).
Above-mentioned route -1 and its improved synthetic method on its basis all have a unreasonable synthesis mould
Four nitrogen-atoms are first introduced to 5- substituted tetrazole (compound -3), behind in rearrangement reaction, and by two therein likes:
Nitrogen-atoms is repelled in the form of nitrogen in outside the molecular structure of compound.This has violated atom economy and has utilized principle.
Route 2 is three-step reaction: first step reaction is that ethyl acetate and hydration hydrazine reaction obtain monosubstituted acethydrazide (chemical combination
Object -5)；Second step reaction, which is that monosubstituted acethydrazide ethyl oxalyl chloride is acylated, obtains key intermediate N, N '-two acyls of asymmetry
Hydrazine (compound -6), last third step reaction obtain product (compound -1) (ginseng with paratoluensulfonyl chloride/TEA dehydration condensation again
Examine the patent document that U.S. Application No. is US2009/0035324).
This route has several drawbacks in that: the first step reacts hydrazine hydrate back flow reaction 4 hours in ethyl acetate, will necessarily produce
Raw the symmetrical diacetyl hydrazine of by-product (compound -7), so as to cause the product monoacylphosphine hydrazine (compound-that is concentrated under reduced pressure that treated
5) there was only 30% yield.
Second step reaction: ethyl oxalyl chloride is as acylating reagent.This is a kind of chemicals of valuableness, for industrial metaplasia
Produce higher cost.In addition, in a humidity environment, either storing still in the reaction, ethyl oxalyl chloride is easy to divide
Solution is oxalic acid mono ethyl ester.Oxalic acid mono ethyl ester is as impurity as reaction dissolvent is brought into reaction in next step until final products 5- first
In base-[1,3,4]-oxadiazoles -2- potassium formate (compound -2), there is larger impact to the quality of final products.
It is stated in patent document US2009/0035324 and chromatographs to obtain the product (compound -6) of second step reaction by column
Yield only has 47%.And column chromatographs this purification process and is not suitable for industrialized mass production.
Moreover, the solvent in second step reaction of route 2 has used methylene chloride.It is methylene chloride low boiling point, volatile, it is one
Kind has the control class chemicals of biggish hepatotoxicity wind agitation and genetoxic.In pharmaceutical production, producer always want to avoid using
Methylene chloride.Because methylene chloride allows existing concentration very low in Workplace, and labour protection requirement is very high.And
Residual quantity of the methylene chloride in drug has strict control, and these requirements both increase the production cost of drug.
J.Dost and H.J.Stein(Journal.Prakt.Chemie., 1985,327:109) report route 3:
But preparation method and the experiment behaviour of starting material oxalic acid mono ethyl ester hydrazides (compound -8) are not mentioned in the document
Make step.
Document mesoxalic acid mono ethyl ester hydrazides (compound -8) and alkyl acyl chloride (such as: chloroacetic chloride R=CH3) in dioxane
In, 45-50 DEG C is reacted 10 hours, and 2- hydrazide group-oxalic acid list alkyl ester (compound -6), yield 82% are obtained.
The present inventor tests the method discovery yield and cannot repeat.And detect reactant discovery have it is more
Two by-products.One is three hydrazides (compound -9), and it is to be understood that this by-product is generated under conditions of this violent
's.
Another by-product is symmetrical diacetyl hydrazine (compound -7).Its Crack cause is the chloroacetic chloride due to high concentration
At high temperature instead of -6 mesoxalic acid alkyl group of compound.This process is exactly so-called acyl exchange reaction.
This two by-products are difficult to remove, and bring into the product reacted below, affect the quality of bulk pharmaceutical chemicals.
Moreover, 2- hydrazide group-oxalic acid list alkyl ester (compound -6) obtains product 5- methyl-[1,3,4]-by dehydration closed-loop
Oxadiazoles -2- alkyl formate (compound -1).A large amount of phosphorus oxychloride (molar ratio is greater than 1:16) is applied in reaction, as
Reaction reagent and as reaction dissolvent, keeps the temperature 1.5 hours at 65 DEG C, yield is only in 37%-45% after separation.
These known routes have several drawbacks in that: yield is low, and reaction condition is violent.For example, 3.0g intermediate (compound-
6) dehydration closed-loop can just obtain required product (compound -1) in 30.0ml POCl3.Being recycled excessive POCl3 can draw
It plays high waste disposal fee to use, increases the risk of industrialized production.Result in the production of target product and its downstream product
It is costly.
Summary of the invention
The present invention provides a kind of 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate synthetic method, this method behaviour
Make simple, high income, suitable for industrialized production.
A kind of synthetic method of 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate, comprising:
Step 1: dialkyl oxalate and hydrazine hydrate, which are carried out ammonolysis reaction, obtains oxalic acid list alkyl ester hydrazides (compound-
8)；
The dialkyl oxalate structure is shown below:
In above formula, R1For C1-C6Alkyl；
The structure of the oxalic acid list alkyl ester hydrazides is shown below:
Compound -8
Step 2: obtained oxalic acid list alkyl ester hydrazides and fatty acid anhydride are carried out acylation reaction, 2- hydrazide group-oxalic acid is obtained
Single alkyl ester (compound -6)；
The 2- hydrazide group-oxalic acid list alkyl ester structure is shown below:
Compound -6
In above formula, R2For C1-C6Alkyl；
Step 3: obtained 2- hydrazide group-oxalic acid list alkyl ester (compound -6) is carried out dehydration condensation reaction, target is obtained
Product 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate (compound -1)；
The 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate structure is shown below:
Compound -1
R in above formula1、R2It is defined as above.
The process of above-mentioned reaction is shown below:
Amide is made from amine, hydrazine or hydrazides can be acylated with three classes acylating reagent (acyl chlorides, acid anhydrides, carboxylate).In three,
Acyl chlorides has strongest acylated ability, and vigorous reaction occurs with amine, hydrazine and even explodes.The activity of acid anhydrides is lower than corresponding acyl
The activity of the activity of chlorine, carboxylate is most weak in three classes acylating agent.
More acylated phenomenons can occur with hydrazine reaction at single hydrazides simultaneously for acyl chlorides and acid anhydrides: react and generate that N- is monoacylated to be easy to
Further acylation obtains N, bis- hydrazides of bis- hydrazides of N- or N, N'-.Substantially being difficult control in reaction process, to have to impurity less
The monoacylated object of N-.
The ammonolysis of carboxylate is a very useful reaction.It, can be with using the acylating reagent reaction that carboxylate is mild in this way
Greatly reduce the ratio of two hydrazides of by-product generated.
Therefore, the first step of process route of the invention is very important.Oxalyl is replaced with mild oxalic acid Arrcostab
The amount of by-product can be effectively reduced in chlorine or oxalic anhydride and at low temperature reaction.Control dropping temperature at -30 DEG C~30 DEG C, so
It is reacted at -10 DEG C~30 DEG C afterwards, may insure fully reacting in this way.
In the first step, the temperature of ammonolysis reaction can according to dialkyl oxalate, solvent selection and change, as excellent
It selects, in the first step, hydrazine hydrate is added by the way of being added dropwise, and it is -30 DEG C~30 DEG C that phase temperature, which is added dropwise, ammonolysis reaction stage temperature
Degree is -10 DEG C~30 DEG C.Further preferred dropwise addition phase temperature is -30 DEG C~-10 DEG C.Further preferred ammonolysis reaction rank
Duan Wendu is -10 DEG C~10 DEG C.
In the first step, the molar ratio of dialkyl oxalate and hydrazine hydrate is 1.0:0.8~1.5, preferably 1.0:0.9~
1.1.Various Arrcostabs can be selected in dialkyl oxalate, preferably, the dialkyl oxalate includes diethy-aceto oxalate, grass
Dimethyl phthalate, dibutyl oxalate or diisopentyl oxalate etc., further preferably diethy-aceto oxalate.That is R1Preferably methyl,
Ethyl, butyl or isopentyl etc., further preferably methyl.
The solvent for being applicable in the first step of the present invention can be selected from one of following: methanol, ethyl alcohol, normal propyl alcohol, isopropanol, positive fourth
Alcohol, sec-butyl alcohol, amylalcohol, 50-95% methanol aqueous solution, 50-95% ethanol water, 50-95% normal propyl alcohol aqueous solution, acetonitrile, or
The mixed system of several above-mentioned solvent different proportion compositions.Preferably one of methanol, ethyl alcohol and acetonitrile or a variety of.
In order to reduce the formation of by-product, second step reaction is also to carry out at low temperature.The fatty acid of specified amount is added dropwise
Acid anhydride is into reaction mass, and control system temperature is -30 DEG C~30 DEG C during dropwise addition.Rear material is added dropwise -10 DEG C~30
DEG C fully reacting.Second step reaction be added dropwise fatty acid anhydride and reaction when temperature can be according to the selection of fatty acid anhydride, solvent
And change, so it is -30 DEG C~30 DEG C that stage control temperature, which is added dropwise, preferably, fatty acid anhydride is added by the way of being added dropwise,
Acylation reaction stage control temperature is -10 DEG C~30 DEG C.As further preferred, it is -30 DEG C~-10 that stage control temperature, which is added dropwise,
℃；Acylation reaction stage control temperature is -10 DEG C~10 DEG C.Then reaction solution is concentrated under reduced pressure to give 2- hydrazide group-oxalic acid list alkane
Ester (compound -6) solid.A variety of organic solvents can be used in second step reaction, and it includes ethyl alcohol, methanol, third that organic solvent, which can be used,
Ketone etc., preferably ethyl alcohol.
To obtain 2- hydrazide group-oxalic acid list alkyl ester product of high-purity, may be selected to the 2- hydrazide group-oxalic acid being concentrated to get
Toluene is added in single alkyl ester (compound -6) solid, stirs material pulp.The by-product that fatty acid anhydride is generated in acylation reaction
Object fatty acid in solid from extracting in toluene phase, the then higher compound -6 of the isolated purity of material filtering.By-product
Fatty acid is dissolved in toluene, is removed as filtrate.In addition, heptane, MIBK(methylisobutylketone), 2- methyl tetrahydro furan
It mutters, hexamethylene, acetonitrile are also the suitable solvent for removing accessory substance aliphatic acid.
The amount of fatty acid anhydride be according to the first step in the amount of dialkyl oxalate be calculated.Dialkyl oxalate:
The molar ratio of fatty acid anhydride is 1.0:1.0~3.0, preferably 1.0:1.1~1.6.Or oxalic acid list can be obtained according to the first step
The amount of alkyl ester hydrazides, which calculates, to be added, preferably, oxalic acid list alkyl ester hydrazides: the molar ratio of oxalic acid list alkyl ester hydrazides be 1:1~
1.5.The fatty acid anhydride used in second step is preferably for acetic anhydride, propionic andydride, n butanoic anhydride and isobutyric anhydride.Further preferably
For acetic anhydride.That is R2Preferably methyl, ethyl, propyl or isopropyl, further preferably methyl.
Third step reaction is 2- hydrazide group-oxalic acid list alkyl ester (compound -6) dehydration closed-loop reaction.By 2- hydrazide group-oxalic acid
Single alkyl ester (compound -6) puts into solvent appropriate, is added after dehydrating agent is stirred and is heated to fully reacting.
In the step, reaction temperature is preferably 50 DEG C~110 DEG C.Reaction 3~24 hours, then the post-processing that cools down, obtain compound -1, receive
Rate is 65%~85%.
Obtained 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate can be purified by purification, can not also be refined
It is directly used in the preparation of 5- methyl-[1,3,4]-oxadiazoles -2- formic acid sylvite (compound -2).
Dehydration closed-loop reaction solvent can be one of selected from following solvent: toluene, normal heptane, MIBK(methylisobutylketone), 2-
Methyltetrahydrofuran, hexamethylene, acetonitrile, dimethylbenzene, 1,3,5- trimethylbenzenes, DMF, DMSO, NMP.Preferably toluene, positive heptan
Alkane, acetonitrile and MIBK.In reaction process, to avoid the generation of side reaction, while lowering energy consumption, step-up temperature can be used, for example,
When using toluene as reaction dissolvent, preferably, being warming up to 80~85 DEG C first, reacts 0.5~1.5 hour, then heat to
100~110 DEG C are reacted 4~5 hours to fully reacting again.When using acetonitrile as reaction dissolvent, since easy solvent itself boils
Point is lower, system directly can be warming up to 70~85 DEG C until the reaction is complete.
Different dehydrating agents can be used for the synthesis of 5- methyl-[1,3,4]-oxadiazoles -2- formic acid esters, such as:
POCl3、POCl3/DMAP、P2O5、SOCl2/ pyridine, trifluoroacetic anhydride (TFAA) and Eaton reagent.Preferably POCl3、POCl3/
DMAP and Eaton reagent.
The present invention is for the first time by POCl3Dehydration closed-loop reagent, which is incorporated as, with DMAP is applied to the synthesis that 5- replaces oxadiazoles
In, the yield of reaction has been significantly increased.
Eaton reagent is also applied to 5- as dehydration closed-loop reagent for the first time and replaced in the synthesis of oxadiazoles by the present invention, greatly
Improve to amplitude the yield of reaction.
According to the difference of dehydrating agent ability and reaction temperature, 2- hydrazide group-oxalic acid list alkyl ester (compound -6): dehydrating agent
Molar ratio can be different, selected in the range of 1.0:0.3~5.0, preferably 1:0.4~1.6.Using POCl3And DMAP
When as dehydrating agent, preferably, the POCl3With DMAP molar ratio be 1:0.001~0.1, further preferably 1:
0.005~0.04.When using Eaton reagent as dehydrating agent, the additional amount of Eaton reagent is every mole of 2- of 500ml~800ml
Hydrazide group-oxalic acid list alkyl ester, i.e. Eaton reagent and 2- hydrazide group-oxalic acid list alkyl ester molar ratio are 3~5:1.
Compared with prior art, the invention has the benefit that
5- alkyl-[1,3,4] of the invention-oxadiazoles -2- alkyl formate synthetic method, by technique itself
It improves, avoids the raw material using risk, explosive, and route novelty, high income, raw material and solvent is cheap, safe operation is simple
Just, it is suitable for industrialized production.
Specific embodiment
In order to keep the present invention apparent understandable, following example elaborates details particularly, but is not used in and limits this hair
Bright protection scope.
Embodiment 1
Oxalic acid mono ethyl ester hydrazides (compound -8, R1=C2H5) preparation
Under nitrogen protection, diethy-aceto oxalate (300.0g, 2.05mol) is dissolved in ethyl alcohol 1400ml, is cooled to -25 DEG C
~-20 DEG C, ethyl alcohol (1050ml) solution of hydrazine hydrate (1 hydrate) (99.6g, 1.96mol, > 98%) is added dropwise.After being added dropwise
Reaction solution is stirred overnight at 0 DEG C~5 DEG C.It is filtered after fully reacting, filter cake is washed with ethyl alcohol 120ml, merging filtrate, is depressurized dense
Be reduced to it is dry, concentrate can use acetonitrile refining, filtering, dry.Obtain ethyl oxalate hydrazides (compound -8) 243.5g.Yield
90.0%。
Above-mentioned reaction can also carry out in other solvents, such as under similarity condition: when selection methanol is reaction dissolvent, chemical combination
- 8 yield of object is 92%；When selection isopropanol is reaction dissolvent, -8 yield of compound is 89%；Select mass percent concentration be
When 95% ethanol water is reaction dissolvent, -8 yield of compound is 94%；When selection acetonitrile is reaction dissolvent, -8 yield of compound
It is 93%.
Embodiment 2
2- hydrazide group-oxalic acid list alkyl ester (compound -6, R1=C2H5,R2=CH3) preparation
Oxalic acid mono ethyl ester hydrazides (264.4g, 2.00mol) is dissolved in ethyl alcohol 1650ml, is cooled to -20 DEG C~-15 DEG C,
It is added dropwise acetic anhydride (255.5g, 2.50mol).After being added dropwise, reaction solution 0 DEG C~5 DEG C stir 4 hours, then at room temperature
Being stirred overnight makes fully reacting.It depressurizes down again and is concentrated to get off-white powder, toluene is added and stirs pulp, filtering.Toluene again
Filter cake is washed, remaining a small amount of acetic acid in filter cake is removed, drying obtains 2- hydrazide group-oxalic acid list alkyl ester 295.8g.Yield is
85.0%.
Other fatty acid anhydrides also can be selected in above-mentioned reaction, such as select n butanoic anhydride, using same condition, 2- hydrazides
Base-oxalic acid list alkyl ester yield is 87%.
Embodiment 3
Use POCl3Make dehydrating agent preparation 5- methyl-[1,3,4] oxadiazoles -2- Ethyl formate (compound -1, R1=C2H5,R2=
CH3).
Under room temperature, nitrogen protection, by 2- hydrazide group-oxalic acid list alkyl ester (compound -6, R1=C2H5,R2=CH3) (85.3g,
Reaction flask 0.49mol) is put into, is added in toluene 250ml, adds POCl3(76.8g, 0.50mol) stirs temperature reaction.When
When temperature rise is to 80 DEG C~85 DEG C in reaction system, flows back, insulation reaction 1 hour, be further continued for being heated to interior temperature 100
DEG C, keeping the temperature 4 hours at this temperature makes fully reacting, then is down to room temperature.
By the reaction solution toluene phase transfer for having cooled to room temperature into separatory funnel, saturation NaHCO is first used3Aqueous solution 25ml
It washs in two times, separates water layer.Then toluene is mutually washed twice with 10% NaCl aqueous solution 30ml again, separates water layer.
Organic layer, which is concentrated under reduced pressure, removes toluene, obtains 5- methyl-[1,3,4] oxadiazoles -2- Ethyl formate 52.4g, yield 68.5%.
1H-NMR(CDCl3): δ 1.39(3H, t, J=8.0Hz), 2.60 (3H, s), 4.45 (2H, q, J=8.0Hz).
LC-MS(M+H):157.06C6H9N2O3。
Embodiment 4
Use POCl3Make dehydrating agent, DMAP is catalyst, and 5- methyl-[1,3,4] oxadiazoles -2- formic acid is prepared in acetonitrile
Ethyl ester (compound -1, R1=C2H5,R2=CH3).
Under room temperature, nitrogen protection, 2- hydrazide group-oxalic acid list alkyl ester (compound -6, R is taken1=C2H5,R2=CH3)
(174.2g, 1.00mol), DMAP (4.9g, 0.04mol) are put into reaction flask, and acetonitrile 430ml is added, adds POCl3
(153.5g, 1.00mol), stirring heating.When reaction system is warming up to 77~82 DEG C, flows back, keep the temperature at this temperature
Make fully reacting, then be cooled to room temperature within 20 hours.
The organic phase of material in reaction flask is transferred in concentrate bottle, is concentrated to dryness, is dissolved and is concentrated with 500ml toluene
Object.Toluene solution is transferred in separatory funnel, first with saturation NaHCO3Aqueous solution 25ml is washed in two times, separates water layer.
Then toluene is mutually washed twice with 10% NaCl aqueous solution 30ml again, separates water layer.Organic layer, which is concentrated under reduced pressure, removes toluene,
Obtain 5- methyl-[1,3,4] oxadiazoles -2- Ethyl formate 124.0g.Yield 79.5%.
Embodiment 5
Use POCl3Make dehydrating agent, DMAP is catalyst, and 5- methyl-[1,3,4] oxadiazoles -2- formic acid is prepared in toluene
Ethyl ester (compound -1, R1=C2H5,R2=CH3).
Under room temperature, nitrogen protection, 2- hydrazide group-oxalic acid list alkyl ester (compound -6, R is taken1=C2H5,R2=CH3)
(174.2g, 1.00mol), DMAP (0.7g, 0.01mol) are placed in a reaction flask, and toluene 348ml is added, adds POCl3
(230.0g, 1.50mol) is slowly stirred temperature reaction material.When reaction system is warming up to 80-85 DEG C, reaction system has one
Fixed backflow phenomenon, insulation reaction 1 hour.It is further continued for being heated to 105-110 DEG C of interior temperature, keeping the temperature 5 hours at this temperature makes instead
Completely, then reaction mass should drop to room temperature.Next experimental implementation obtains 5- methyl-[1,3,4] oxadiazoles -2- first with example 3
Acetoacetic ester 128.7g(yield 82.5%).
Embodiment 6
5- methyl-[1,3,4] oxadiazoles -2- Ethyl formate (chemical combination is prepared with Eaton reagent (No. CAS: 39394-84-8)
Object -1, R1=C2H5,R2=CH3).
Under room temperature, nitrogen protection, Eaton reagent 360ml(about 2.27mol) is put into pre-dry reaction flask,
Again by 2- hydrazide group-oxalic acid list alkyl ester (compound -1, R under stronger nitrogen protection1=C2H5,R2=CH3) (87.1g,
It is rapidly joined under 0.49mol) stirring.Reaction system, which will be slow, is warming up to 30-35 DEG C.When reaction system stops from heat release, then
Slow external heat reaction system, being warming up to 55-60 DEG C of interior temperature and keeping the temperature 5 hours makes fully reacting.Then hypothermic response material
To 5-10 DEG C or so, reaction mass is stirred down and is slowly put into 3000ml ice water, is adjusting pH to 7.5- with 30% NaOH
8.0.Solution is extracted twice with 300ml isopropyl acetate.Organic layer is concentrated under reduced pressure to give product and dislikes two for 5- methyl-[1,3,4]
Azoles -2- Ethyl formate 132.7g, yield 85.0%.
Embodiment 7
The preparation of 5- methyl-[1,3,4] oxadiazoles -2- potassium formate (compound -2)
5- methyl-[1,3,4] oxadiazoles -2- Ethyl formate (compound -1) (200g, 1.28mol) is taken to be dissolved in nothing at room temperature
In water-ethanol 1.8L, solution is cooled to 10 DEG C, is added dropwise KOH solution (360g, 20%), is added dropwise and is stirred at room temperature 40 minutes,
Then it filters, filter cake is washed with ethyl alcohol 500ml, then is washed with methyl tertiary butyl ether(MTBE).It is dried under reduced pressure to obtain 5- methyl-[1,3,4]
Oxadiazoles -2- potassium formate (compound -2) 202.0g, yield 95.0%.
1H-NMR(D2O): δ 2.47 (3H, s);
13C-NMR(D2O): δ 7.99,156.7,158.9,164.3.
Claims (6)
1. a kind of 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate synthetic method, comprising:
Step 1: dialkyl oxalate and hydrazine hydrate, which are carried out ammonolysis reaction, obtains oxalic acid list alkyl ester hydrazides；The oxalic acid dioxane
Base ester and the molar ratio of hydrazine hydrate are 1.0:0.9~1.1；The ammonolysis reaction filters afterwards completely；
The dialkyl oxalate structure is shown below:
In above formula, R1For C1-C6Alkyl；
The structure of the oxalic acid list alkyl ester hydrazides is shown below:
Step 2: obtained oxalic acid list alkyl ester hydrazides and fatty acid anhydride are carried out acylation reaction, 2- hydrazide group-oxalic acid list alkane is obtained
Ester；The fatty acid anhydride is acetic anhydride；
Toluene is added into the 2- hydrazide group being concentrated to get-oxalic acid list alkyl ester, the pair that fatty acid anhydride is generated in acylation reaction
Product fatty acid extracts in toluene from solid；
The 2- hydrazide group-oxalic acid list alkyl ester structure is shown below:
In above formula, R2For methyl；
Step 3: obtained 2- hydrazide group-oxalic acid list alkyl ester is carried out dehydration condensation reaction, obtain target product 5- alkyl-[1,
3,4]-oxadiazoles -2- alkyl formate；Solvent used by the dehydration condensation reacts is toluene；2- hydrazide group-the oxalic acid
Single alkyl ester and the molar ratio of dehydrating agent are 1:0.4~1.6；The dehydrating agent is POCl3/ DMAP, POCl3With DMAP molar ratio
For 1:0.001~0.1；
The 5- alkyl-[1,3,4]-oxadiazoles -2- alkyl formate structure is shown below:
Wherein, R2For methyl.
2. 5- alkyl-[1,3,4] according to claim 1-oxadiazoles-2- alkyl formate synthetic method, feature
It is, in the first step, reaction dissolvent is methanol, ethyl alcohol, normal propyl alcohol, isopropanol, n-butanol, sec-butyl alcohol, amylalcohol, mass percent
Content is 50~95% methanol aqueous solutions, mass percentage content is 50~95% ethanol waters, mass percentage content is
One of 50~95% normal propyl alcohol aqueous solutions, acetonitrile are a variety of.
3. 5- alkyl-[1,3,4] according to claim 1-oxadiazoles-2- alkyl formate synthetic method, feature
It is, in the first step, hydrazine hydrate is added by the way of being added dropwise, and it is -30 DEG C~30 DEG C that phase temperature, which is added dropwise, the ammonolysis reaction stage
Temperature is -10 DEG C~30 DEG C.
4. 5- alkyl-[1,3,4] according to claim 1-oxadiazoles-2- alkyl formate synthetic method, feature
It is, the molar ratio of the dialkyl oxalate and fatty acid anhydride is 1.0:1.0~3.0.
5. 5- alkyl-[1,3,4] according to claim 1-oxadiazoles-2- alkyl formate synthetic method, feature
It is, in second step, fatty acid anhydride is added by the way of being added dropwise, and it is -30 DEG C~30 DEG C that stage control temperature, which is added dropwise, acylated anti-
Answering stage control temperature is -10 DEG C~30 DEG C.
6. 5- alkyl-[1,3,4] according to claim 1-oxadiazoles-2- alkyl formate synthetic method, feature
It is, the reaction temperature of the dehydration condensation reaction is 50 DEG C~110 DEG C.
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